Restenosis is the narrowing of the blood vessels, which can occur after injury to the vessel wall, for example, injury caused by surgical techniques employed to achieve revascularization. Restenosis can occur following a number of surgical procedures, for example, balloon angioplasty, transplant surgery, vein grafting, coronary by-pass grafting, and most frequently by percutaneous transluminal vascular intervention (PTVI). Unfortunately, many of these techniques are plagued by a high incidence of vessel renarrowing or restenosis. Restenosis is mediated by internal hyperplasia and is characterized by excessive proliferation of vascular smooth muscle cells in the walls of the treated blood vessel.
The vascular changes observed following PTVI involve a cascade of molecular and cellular events occurring within the vessel wall involving the release of a variety of vasoactive, thrombogenic, and mitogenic factors. These factors, acting in concert, stimulate the migration and proliferation of vascular smooth muscle cells (VSMC) and production of extracellular matrix material, which accumulate to occlude the blood vessel. Within this cascade are two processes that stand out as potential therapeutic targets; vascular remodeling and neointimal hyperplasia. Vascular remodeling, defined as any enduring change in the size and/or composition of a blood vessel, allows adaptation and repair. On the other hand, inappropriate remodeling, including its absence, underlies the pathogenesis of major cardiovascular diseases, such as atherosclerosis and restenosis. Experimental evidence acquired in vitro and in vivo suggests that the major drivers of vascular remodeling: inflammation, partially a result of oxidative stress and free radical formation; and inappropriate cell migration and proliferation are all key regulators in the remodeling process and ultimately lead to vessel restenosis.
It has been demonstrated that cytokines can trigger much of the inflammatory component of injury. Cytokines are molecules that mediate the migration of leukocytes into inflamed tissues and control the inflammatory reactions in various immune-mediated diseases. Both in animal models and in human specimens, chemokine expression is associated with atherosclerotic lesion development and vascular remodeling and restenosis after angioplasty. Activation of these inflammatory and procoagulant mechanisms is thought to contribute significantly to the initiation of restenosis. During this process, expression of tissue factor (TF) represents another one of the major physiologic triggers of coagulation that results in thrombus formation and the generation of additional signals leading to VSMC proliferation and migration.
In addition, the activity of NF-kappa B, a transcriptional regulatory factor, has been demonstrated to be involved in the inflammatory activation of endothelial cells and their adhesiveness and also appears to regulate apoptosis in smooth muscle cells (SMC) by coordinating anti-apoptotic processes. The level of activity of NF-kappa B has been shown to be enhanced within human atheromas or following angioplasty as compared with healthy vessels. Thus, the inhibition of NF-kappa B mobilization through therapeutic intervention can act to suppress endothelial activation and to induce SMC apoptosis. As mentioned, free radicals and oxidant stress also play a role in vascular pathology. Increased oxidative stress is a major characteristic of restenosis after angioplasty. The oxidative stress is mainly created by oxidants such as reactive oxygen species (ROS), which are assumed to play a role in neointima formation and smooth muscle proliferation. Once oxidant stress is invoked, characteristic pathophysiologic features follow, namely compromised vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation, all perpetrators in the restenosis process. Evidence suggests that this complex cascade of molecular and cellular events occurring within the vessel wall culminates in cellular proliferation.
What is needed is a method of preventing or treating restenosis and other vascular proliferative disorders. The compositions and methods disclosed herein meet this and other needs.